Why Is Stereochemistry Important In Drug Design

Chiral drugs, sold as single enantiomers, either for an economical or regulatory reason, are likely to dominate drug markets in the near future. Pharmaceutical companies see enantiomers as a way of prolonging the patent life of their existing racemic drugs by patenting and then marketing the active enantiomer thereby undercutting competition from generic drug sales. In addition, some companies see this switching from racemate to single active enantiomer as a way into the drug market. However, these are not the only reasons for testing individual enantiomers of chiral drugs. Lessons learned from mistakes made by marketing racemic drugs also play a part, such as the tragic case of thalidomide (Figure 5.8). Racemic thalidomide was developed in the 1950s and was used as a sleeping pill and to treat morning sickness. Unfortunately, the drug had serious side effects as it was found to be teratogenic causing fetal abnormalities. It was later discovered in tests with mice that the (S)-enantiomer possessed the teratogenic activity while the (R)-enantiomer possessed the sedative activity. However, subsequent studies revealed that the enantiomers racemise under physiological conditions. Despite this, thalidomide brought the role of chirality in drug development into the spotlight. Recently, thalidomide has hit the headlines again as the use of the racemate for treatment of leprosy has been approved by the Food and Drug Administration (FDA) but only under the strictest of guidelines. It appears that thalidomide may also have therapeutic utility in the treatment of AIDS-related disorders and tuberculosis.

The FDA strongly urges companies to evaluate both the racemates and the corresponding individual enantiomers as new drugs. Thus, even if a drug is to be sold as a racemate, the individual enantiomers need to be evaluated, which increases the cost and timescale of drug development. Therefore, synthesis of single enantiomeric drugs is becoming a priority.

It should be noted that not only the pharmacodynamic aspects are important in the discussion of the activity of chiral drugs. Pharmacokinetics is also affected as the absorption and clearance of drugs involves interaction with enzymes and transport proteins. Thus, the individual enantiomers of a chiral drug may be metabolized by enzymes at different rates and may be transformed into different chemical entities. As a result of these considerations, it is very important that individual enantiomers of chiral drugs are tested in the clinic.

Ariens, a pioneer in the field of enantioselective drug actions, has proposed that the active enantiomer of a chiral drug be termed the eutomer while the less active enantiomer should be termed the distomer. The eudismic ratio (ER) is defined as the ratio of the activity of the eutomer to that of the distomer. The presence of the distomer in the racemic drug can have a number of consequences for the biological activity.

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